The concept of cancer stem cells has tremendous implications for the management of cancer [Pan, et al., Future Oncol (2006) 2:723-731; and Misaghian, et al., Leukemia (2009) 23:25-42]. Cancer stem cells have been identified in both hematological and solid malignancies, suggesting that the existence of cancer stem cells is a common feature of most malignancies. These cells can self-renew and regenerate more cancer cells. In order to effectively treat and prevent cancer, cancer stem cells must be reduced or eliminated. However, cancer stem cells exhibit a higher level of chemoresistance compared to their progeny cancer cells [Terpstra, et al., Blood (1996) 88:1944-1950; and Copland, et al., Blood (2006) 107:4532-4539]. The present invention is based, in part, on the demonstration of the feasibility of using drug-loaded nanoparticles that are engineered to bind with high affinity and specificity to acute myeloid leukemia (AML) stem cells (LSC).
Under present protocols, chemoresistance of LSC can be overcome with high-dose chemotherapy followed by bone marrow transplantation. However, high-dose chemotherapy is associated with severe toxicity and high therapy-related mortality. Many patients are not eligible for this treatment because of co-morbidities. This is especially true for AML patients with a median age at diagnosis of 60 to 65 years and usually associated with multiple co-morbidities. For bone marrow transplantation, autologous bone marrow or stem cells are usually not used because of contamination by LSC. Allogeneic hematopoietic stem cell transplantation is often associated with severe graft-versus-host disease, and is commonly not offered to elderly patients.
Among cancer stem cell types, AML LSC have been best characterized. Many of the cell surface molecules on LSC are known. For example, the C-type lectin-like molecule-1 (CLL1) is known to be preferentially expressed on most AML LSC. Even though CLL1 is also expressed on CD38(+) myeloid progenitor cells, it is not on CD34(+)/CD38(−) hematopoietic stem cells [Bakker, et al., Cancer Res (2004) 64:8443-8450; and van Rhenen et al., Blood (2007) 110:2659-2666]. It has been shown that CLL1 can be potentially targeted for the treatment of AML [Zhao, et al., Haematologica (2010) 95:71-78].
Recently, a biocompatible nanomicelle drug delivery system comprised of a unique amphiphilic polymers called telodendrimers was developed [Xiao, et al., Biomaterials (2009) 30:6006-6016; Luo, et al., Bioconjug Chem (2010) 21:1216-1224]. Telodendrimers consist of cholic acid, lysine and polyethylene glycol (PEG) covalently conjugated together, which impart the ability to self-assemble into a water-soluble spheroid with a hydrophobic core capable of sequestering many types of drugs. Cholic acid, a primary component of bile acid, possesses a facial amphiphilic structure: a rigid steroid scaffold with four hydrophilic groups on one surface, and hydrophobic methyl groups on the other surface of the scaffold. Lysine is a natural amino acid. PEG is biocompatible and has been used to improve the pharmacokinetics of therapeutic drugs. This nanocarrier system has many attractive characteristics for drug delivery, such as high drug loading capacity, narrow polydispersity, well-defined structure, easy chemical modification, superior physical, chemical stability and biocompatibility.
The present invention is based, in part on the discovery of a series of peptides via the phage-display library method that bind specifically to CLL1. One of these ligands, CLL1-L1, was used to decorate the surface of nanomicelles to form a targeting nanoplatform that we named “LSC-targeting nanomicelles.” Unlike solid tumors that primarily reside at the extravascular space and are accessible by nanotherapeutics mainly through enhanced permeability and retention effect, LSC and leukemic cells reside primarily inside blood vessels and bone marrow that are directly accessible by nanotherapeutics through intravenous administration. Data provided herein demonstrate that targeting nanomicelles displaying CLL1-L1 bind to the surface of cells expressing CLL1, and deliver the nanomicelles and their effector cargo into the target cells.